Risk of Acute Liver Injury With Antiretroviral

2 downloads 0 Views 249KB Size Report
bilirubinemia [9]) and acute liver failure (ALF). Prior studies ... immune deficiency syndrome (AIDS)-related diagnosis. ...... Cardiohepatic interactions in heart fail-.
Open Forum Infectious Diseases MAJOR ARTICLE

Risk of Acute Liver Injury With Antiretroviral Therapy by Viral Hepatitis Status Charitha Gowda,1,2 Craig W. Newcomb,3 Qing Liu,3 Dena M. Carbonari,3,4 James D. Lewis,3,4,5 Kimberly A. Forde,3,4,5 David S. Goldberg,3,4,5 K. Rajender Reddy,4,5 Jason A. Roy,3,4 Amy R. Marks,6 Jennifer L. Schneider,6 Jay R. Kostman,7 Janet P. Tate,8,9 Joseph K. Lim,8,9 Amy C. Justice,8,9 Matthew Bidwell Goetz,10 Douglas A. Corley,6 and Vincent Lo Re III3,4,11 1

Division of Pediatric Infectious Diseases, Nationwide Children’s Hospital, Columbus, Ohio; 2Department of Pediatrics, Ohio State University College of Medicine, Columbus; 3Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; 4Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia; 5Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia; 6Division of Research, Kaiser Permanente Northern California, Oakland; 7Jonathan Lax Treatment Center, Philadelphia FIGHT, Pennsylvania; 8VA Connecticut Healthcare System, West Haven, Connecticut; 9Yale University School of Medicine, New Haven, Connecticut; 10VA Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA, Los Angeles, California; and 11Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia

Background.  The risk of hepatotoxicity with antiretroviral therapy (ART) remains unknown. We determined the comparative risk of acute liver injury (ALI) for antiretroviral drugs, classes, and regimens, by viral hepatitis status. Methods.  We followed a cohort of 10 083 human immunodeficiency virus (HIV)-infected persons in Kaiser Permanente Northern California (n = 2099) from 2004 to 2010 and the Veterans Aging Cohort Study (n = 7984) from 2004 to 2012. Within the first year of ART, we determined occurrence of (1) liver aminotransferases >200 U/L and (2) severe ALI (coagulopathy with hyperbilirubinemia). We used Cox regression to determine hazard ratios (HRs) with 95% confidence intervals (CIs) of endpoints among initiators of nucleos(t)ide analogue combinations, antiretroviral classes, and ART regimens, all stratified by viral hepatitis status. Results.  Liver aminotransferases >200 U/L developed in 206 (2%) persons and occurred more frequently among HIV/viral hepatitis-coinfected than HIV-monoinfected persons (116.1 vs 20.7 events/1000 person-years; P 200 U/L after initiation with a protease inhibitor than nonnucleoside reverse-transcriptase inhibitor (HR, 2.01; 95% CI, 1.36–2.96). Severe ALI (30 events; 0.3%) occurred more frequently in coinfected persons (15.9 vs 3.1 events/1000 person-years; P 200 U/L (~5 times the upper limit of normal [ULN] of the assays used), a threshold that represents clinically important hepatic injury [20] and ~10 times what has been considered normal liver aminotransferase levels for males (30 U/L) and females (19 U/L) [21]. As a secondary endpoint, we determined incident grade 3 or 4 aminotransferase elevations determined by the toxicity grade scale used by the AIDS Clinical Trials Group [22], an outcome evaluated in prior studies of antiretroviral-induced ALI [10, 11, 14]. As was done in those studies [10, 11, 14], patients with pre-ART aminotransferases below ULN (ALT, 36 IU/L; AST, 40 IU/L) were classified, based on changes relative to ULN, as having incident grade 3 (>5 times ULN) or grade 4 (>10 times ULN) elevations. Patients with pre-ART aminotransferases above ULN were classified, based on changes relative to the baseline value, as having incident grade 3 (>3.5 times baseline) or grade 4 (>5 times baseline) elevations. Patients who did not have ALT/AST measured before ART initiation were excluded from analyses of grade 3/4 aminotransferase elevations. Second, we evaluated severe ALI, defined by development of both international normalized ratio (INR) ≥1.5 and total bilirubin >2 times ULN in an inpatient or outpatient setting within 30  days of each other [23]. This definition indicates severe hepatic dysfunction and has been used by the US Food and Drug Administration’s Sentinel Initiative to assess serious drug-induced hepatotoxicity in the postmarketing setting [23]. Finally, we evaluated incident ALF among ART initiators without viral hepatitis, because pre-existing liver disease precludes an ALF diagnosis [24]. Acute liver failure was defined by coagulopathy (INR ≥1.5) plus either hepatic encephalopathy or liver transplantation [24]. Data Collection

Baseline clinical data included the following: age, sex, race, obesity (body mass index >30 kg/m2), alcohol dependence/abuse, cancer (excluding nonmelanoma skin cancers), diabetes mellitus, heart failure, and ART regimen. Alcohol dependence/abuse

[25] and heart failure [26] were defined by validated ICD-9 diagnoses. Within KPNC, diabetes and cancer were determined by registries. Within VACS, diabetes was defined by random glucose ≥200  mg/dL, ICD-9 diagnosis, and/or antidiabetic medication use [27], and cancer was determined by ICD-9 diagnosis. Baseline laboratory data included ALT, AST, INR, total bilirubin, platelets, pre-ART CD4 count and HIV RNA, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, and HCV RNA. To minimize misclassification of viral hepatitis status, patients who ever had a positive HBsAg, HCV antibody, or HCV RNA during the study period were classified as viral hepatitis-coinfected. Data collected during follow-up included outpatient and inpatient ALT, AST, INR, and total bilirubin. We determined ALF events among patients without viral hepatitis using a method we previously described [9, 28]. Patients were screened for potential ALF if, during the year after ART initiation, they had the following: (1) a hospital ICD-9 diagnosis suggestive of ALF (Supplementary Appendix 1)  and (2) both an inpatient INR ≥1.5 and peak total bilirubin ≥5.0 mg/dL. Hospital records of these patients were independently reviewed by 2 hepatologists (K.A.F.  and D.S.G.). Acute liver failure was confirmed if a patient was hospitalized and had (1) no chronic liver disease, (2) coagulopathy (INR ≥1.5), and (3) either hepatic encephalopathy or liver transplantation [24]. Disagreements in ALF classification were arbitrated by a third hepatologist (K.R.R.).

Received outpatient antiretroviral therapy within 365 days prior to index datea (n = 3 622) Age200 U/L Among Initiators of Antiretroviral Drugs and Regimens Within Kaiser Permanente Northern California (2004–2010) and the Veterans Aging Cohort Study (2004–2012), Stratified by the Presence of Viral Hepatitis Coinfection Without Viral Hepatitis Coinfection

Regimen/Drug Overall

No. No. Exposed Events Person-Time

With Viral Hepatitis Coinfection

Cumulative Incidence at 1 Year/100 Persons (95% CI)

Incidence Rate, Events/1000 Person-Years (95% CI)

No. Exposed

No. PersonEvents Time

Cumulative Incidence at 1 Year/100 Persons (95% CI)

Incidence Rate, Events/1000 Person-Years (95% CI)

7970

93

4488

1.7 (1.4–2.2)

20.7 (16.7–25.4)

2113

113

973

9.0 (7.4–11.0)

116.1 (95.7–139.6)

5762

66

3464

1.6 (1.3–2.1)

19.1 (14.7–24.2)

1343

73

674

8.3 (6.6–10.6)

108.3 (84.9–136.2)

NRTI Components TDF/FTC or TDF/3TC ABC/3TC

392

5

211

2.2 (0.9–5.4)

23.6 (7.7–55.2)

162

6

71

3TC/ZDV

1032

9

481

1.3 (0.6–2.7)

18.7 (8.6–35.5)

344

20

129

12.9 (7.7–21.0)

155.0 (94.7–239.3)

784

13

332

2.8 (1.6–5.1)

39.2 (20.9–67.0)

264

14

100

13.3 (7.2–23.9)

140.7 (76.9–236.0)

Othera

5.9 (2.5–13.5)

84.9 (31.1–184.7)

Antiretroviral Class Non-NRTI

4937

59

2948

1.7 (1.3–2.3)

20.0 (15.2–25.8)

1148

47

568

6.9 (5.1–9.3)

82.7 (60.7–109.9)

PI

2520

25

1299

1.5 (1.0–2.3)

19.2 (12.5–28.4)

833

59

356

12.0 (9.1–15.6)

165.8 (126.2–213.9)

INSTI

195

5

112

3.4 (1.3–8.6)

44.7 (14.5–104.4)

33

1

14

8.3 (1.2–46.1)

72.8 (1.8–405.8)

Otherb

318

4

129

2.3 (0.8–7.1)

31.1 (8.5–79.6)

99

6

35

12.2 (4.5–30.3)

170.5 (62.6–371.1)

Commonly Used Regimens 3697

42

2320

1.6 (1.2–2.3)

18.1 (13.0–24.5)

761

30

401

6.1 (4.2–8.8)

74.7 (50.4–106.7)

ATV/r + TDF/FTC

EFV/TDF/FTC

854

11

511

1.8 (0.9–3.3)

21.5 (10.7–38.5)

256

18

124

8.6 (5.5–13.5)

144.7 (85.8–228.8)

EFV + 3TC/ZDV

556

2

270

0.8 (0.2–3.7)

7.4 (0.9–26.7)

189

8

71

8.4 (3.9–17.4)

112.2 (48.4–221.0)

LPV/r + TDF/FTC

276

3

131

1.2 (0.4–3.5)

22.8 (4.7–66.7)

90

7

39

14.1 (6.8–28.2)

179.2 (72.1–369.3)

LPV/r + 3TC/ZDV

221

1

95

1.0 (0.1–6.6)

10.5 (0.3–58.7)

70

6

25

20.4 (7.7–47.9)

238.1 (87.4–518.3)

DRV/r + TDF/FTC

224

1

119

0.5 (0.1–3.2)

8.4 (0.2–46.6)

46

5

22

16.1 (6.7–36.0)

230.1 (74.7–536.9) 117.8 (24.3–344.2)

ATV/r + ABC/3TC

150

2

80

2.3 (0.6–9.4)

24.9 (3.0–89.8)

55

3

25

7.4 (2.4–21.7)

RAL + TDF/FTC

174

5

102

3.7 (1.4–9.3)

49.1 (16.0–114.6)

28

1

13

8.3 (1.2–46.1)

77.0 (2.0–429.2)

EFV + TDF/3TC

126

1

70

1.9 (0.3–12.6) 14.3 (0.4–79.6)

30

1

15

4.8 (0.7–29.3)

68.0 (1.7–379.1)

EFV + ABC/3TC

113

2

66

2.7 (0.6–11.0) 30.3 (3.7–109.5)

41

1

19

2.4 (0.3–16.1)

52.2 (1.3–290.6)

Abbreviations: 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; CI, confidence interval; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; LPV, lopinavir; NRTI, nucleos(t)ide reverse-transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; r, ritonavir; RAL, raltegravir; TDF, tenofovir; ZDV, zidovudine. a

“Other” category includes regimens with 1 antiretroviral class.

than KPNC members (Table 1). Median pre-ART CD4, pre-ART HIV RNA, and baseline ALT were similar between the groups. Risk of Liver Aminotransferase Elevations

During the study period, 206 patients (n = 10 083; 2.0%) developed aminotransferases >200 U/L and 178 (n = 9542; 1.9%) developed grade 3/4 aminotransferase elevations. Viral hepatitis-coinfected patients had higher rates of both aminotransferases >200 U/L (Table  2; Supplementary Appendix 2)  and grade 3/4 elevations (Supplementary Appendix 3)  than HIV-monoinfected individuals. Because the 2 aminotransferase elevation outcomes yielded comparable results, multivariable analyses were performed using the primary endpoint of aminotransferases >200 U/L. Risk With Nucleos(t)ide Reverse-Transcriptase Inhibitor Combinations

Absolute risks and rates of aminotransferases >200 U/L for initiators of different NRTI combinations were similar among HIV-monoinfected and HIV/viral hepatitis-coinfected patients (Table  2). Relative hazards of this outcome

associated with different NRTI combinations did not differ by viral hepatitis status (test of interaction, P > .20). Among HIV-monoinfected and viral hepatitis-coinfected persons, initiators of abacavir/lamivudine and zidovudine/lamivudine did not have a greater risk of aminotransferases >200 U/L versus tenofovir/emtricitabine (or lamivudine) initiators, after adjustment for baseline ALT, year of ART initiation, and data source (Figure 2, Model A). Risk With Antiretroviral Classes

Among HIV-monoinfected patients, absolute risks and rates of aminotransferases >200 U/L were similar for initiators of PI, non-NRTI, and INSTI classes (Table 2). Among viral hepatitis-coinfected patients, the rate of aminotransferases >200 U/L was higher for initiators of PI-based ART (165.8 [95% CI, 126.2–213.9] events/1000 person-years) than initiators of non-NRTI-based ART (82.7 [95% CI, 60.7–109.9] events/1000 person-years; P  200 U/L Acute Liver Injury Associated With Antiretrovirals  •  OFID • 5

Model (A): By NRTI Components

Model (C): By Regimen 1.19 (0.16, 8.89)

1.09 (0.59, 2.01)

1.53 (0.80, 2.93)

Othera

2.20 (0.84, 5.79)

1.13 (0.65, 1.96) 0.75 (0.35, 1.60)

2.58 (1.02, 6.57)

3TC/ZDV

0.42 (0.06, 3.13)

0.68 (0.29, 1.57) 1.19 (0.47, 2.97)

ABC/3TC

Adjustedb Hazard Ratio (95% Confidence Interval)

1.13 (0.34, 3.75)

0.37 (0.05, 2.74)

5

Model (B): By Antiretroviral Class Otherc

INSTI-based

ATV/r + TDF/FTC

1.24 (0.52, 2.96) 0.28 (0.06, 1.25)

PI-based

Adjustedb Hazard Ratio (95% Confidence Interval)

EFV + 3TC/ZDV

EFV + TDF/FTC (Reference)

Non-NRTI-based (Reference) 0

ATV/r + ABC/3TC

2.02 (1.11, 3.67) 1.15 (0.59, 2.25)

2.01 (1.36, 2.96) 0.87 (0.54, 1.39)

DRV/r + TDF/FTC

1.47 (0.45, 4.83) 1.36 (0.32, 5.69)

0.98 (0.13, 7.22) 1.98 (0.76, 5.15)

LPV/r + TDF/FTC

4.25 (1.45, 12.51)

2.14 (0.91, 5.05) 1.25 (0.45, 3.45)

LPV/r + 3TC/ZDV

2.12 (0.92, 4.85)

TDF/FTC or TDF/3TC (Reference) 0

RAL + TDF/FTC

10

0

Adjustedb Hazard Ratio (95% Confidence Interval)

15

Viral hepatitis coinfection Without viral hepatitis

Figure 2.  Comparative risk of liver aminotransferase levels >200 U/L among users of different nucleoside reverse-transcriptase inhibitor (NRTI) combinations (Model A), antiretroviral classes (Model B), and antiretroviral regimens (Model C). a“Other” includes regimens with 40 U/L, calendar year of antiretroviral therapy initiation, and data source. cOther refers to regimens with none or >1 of the listed antiretroviral class. ABC, abacavir; ATV/r, boosted atazanvir; DRV/r, boosted darunavir; EFV, efavirenz; FTC, emtricitabine; INSTI, integrase inhibitor; LPV/r, boosted lopinavir; PI, protease inhibitor; TDF, tenofovir; ZDV, zidovudine; 3TC, lamivudine.

associated with antiretroviral classes differed by viral hepatitis status (test of interaction, P = .05). Among HIV-monoinfected persons, adjusted HRs did not differ between antiretroviral classes. However, among viral hepatitis-coinfected persons, those who initiated a PI-based regimen had a higher risk of aminotransferases >200 U/L than those initiating non-NRTIbased regimens (HR, 2.01; 95% CI, 1.36–2.96) (Figure 2, Model B). Among coinfected patients, initiation of INSTI-based ART was not associated with a higher risk of aminotransferases >200 U/L versus non-NRTI-based ART (HR, 0.98; 95% CI, 0.13–7.22).

significant differences in the risk of aminotransferases >200 U/L associated with initiation of these regimens compared with efavirenz plus tenofovir/emtricitabine, after adjustment for baseline ALT, year of ART initiation, and data source (Figure 2, Model C). Among viral hepatitis-coinfected individuals, there was a higher risk of aminotransferases >200 U/L associated with initiation of darunavir/ritonavir plus tenofovir/emtricitabine (HR, 4.25; 95% CI, 1.45–12.51), atazanavir/ritonavir plus tenofovir/emtricitabine (HR, 2.02; 95% CI, 1.11–3.67), and lopinavir/ritonavir plus zidovudine/lamivudine (HR, 2.58; 95% CI, 1.02–6.57) compared with efavirenz plus tenofovir/emtricitabine.

Risk With Antiretroviral Therapy Regimens

Severe Acute Liver Injury and Acute Liver Failure

Between 2004 and 2012, the most commonly prescribed ART regimens were as follows: efavirenz plus tenofovir/emtricitabine (44.2%) or zidovudine/lamivudine (7.4%); atazanavir/ritonavir plus tenofovir/emtricitabine (11.0%) or abacavir/lamivudine (2.0%); lopinavir/ritonavir plus tenofovir/emtricitabine (3.6%) or zidovudine/lamivudine (2.9%); darunavir/ritonavir plus tenofovir/emtricitabine (2.7%); and raltegravir plus tenofovir/ emtricitabine (2.0%). Table  2 presents the absolute risks and rates of aminotransferases >200 U/L for these regimens, stratified by viral hepatitis status. Hazard ratios for different ART regimens did not differ by viral hepatitis status (test of interaction, P > .20). Among HIV-monoinfected persons, there were no

Thirty (0.3%) patients developed severe ALI. Viral hepatitis-coinfected individuals had a higher rate of severe ALI than those without viral hepatitis (Table 3; Supplementary Appendix 4). Severe ALI events were too rare to allow evaluation within multivariable models. Among the 7970 patients without viral hepatitis, none developed ALF within the first year of ART initiation.

6 • OFID • Gowda et al

Risk Factors for Acute Liver Injury Events

Factors associated with development of aminotransferases >200 U/L included viral hepatitis and baseline ALT >40 U/L (Table 4). Viral hepatitis, heart failure, age >50 years, and higher baseline HIV RNA were associated with severe ALI (Table 4).

Table 3.  Cumulative Incidences and Incidence Rates of Severe Acute Liver Injury Among Initiators of Antiretroviral Drugs and Regimens Within Kaiser Permanente Northern California (2004–2010) and the Veterans Aging Cohort Study (2004–2012), Stratified by the Presence of Viral Hepatitis Coinfection Without Viral Hepatitis Coinfection

With Viral Hepatitis Coinfection

No. Exposed

No. Events

Person-Time

Cumulative Incidence at 1 Year/100 Persons (95% CI)

7970

14

4515

0.2 (0.1–0.4)

3.1 (1.7–5.2)

2113

16

1005

1.2 (0.7–2.1)

15.9 (9.1–25.9)

5762

12

3486

0.3 (0.1–0.5)

3.4 (1.8–6.0)

1343

9

695

1.1 (0.5–2.2)

12.9 (5.9–24.6)

ABC/3TC

392

0

212

0.0 (0.0–0.0)

0.0 (0.0–14.1)

162

2

72

1.4 (0.4–5.8)

27.8 (3.4–100.5)

3TC/ZDV

1032

0

482

0.0 (0.0–0.0)

0.0 (0.0–6.2)

344

3

135

1.7 (0.5–6.0)

22.2 (4.6–65.0)

Othera

5762

2

334

0.3 (0.1–1.0)

6.0 (0.7–21.6)

264

2

103

0.8 (0.2–3.1)

19.4 (2.4–70.2)

Regimen/Drug Overall

Incidence Rate, Events/1000 Person-Years (95% CI)

No. Exposed

No. Events

Person-Time

Cumulative Incidence at 1 Year/100 Persons (95% CI)

Incidence Rate, Events/1000 Person-Years (95% CI)

NRTI Components TDF/FTC or TDF/3TC

Antiretroviral Class Non-NRTI

4937

4

2968

0.1 (0.0–0.3)

1.3 (0.4–3.5)

1148

10

581

1.5 (0.7–3.0)

17.2 (8.3–31.7)

PI

2520

10

1303

0.5 (0.3–0.9)

7.7 (3.7–14.1)

833

5

373

0.7 (0.3–1.6)

13.4 (4.3–31.3)

INSTI

195

0

114

0.0 (0.0–0.0)

0.0 (0.0–26.3)

33

0

14

0.0 (0.0–0.0)

0.0 (0.0–210.8)

Otherb

318

0

130

0.0 (0.0–0.0)

0.0 (0.0–23.1)

99

1

37

1.1 (0.2–7.4)

27.1 (0.7–151.1) 14.7 (5.4–31.9)

Commonly Used Regimens EFV/TDF/FTC

3697

4

2337

0.1 (0.0–0.4)

1.7 (0.5–4.4)

761

6

409

1.4 (0.6–3.4)

ATV/r + TDF/FTC

854

5

513

0.8 (0.3–1.9)

9.7 (3.2–22.7)

256

1

132

0.4 (0.1–2.8)

EFV + 3TC/ZDV

556

0

271

0.0 (0.0–0.0)

0.0 (0.0–11.1)

189

3

74

3.2 (0.9–10.9)

LPV/r + TDF/FTC

276

2

132

0.7 (0.2–2.9)

15.2 (1.8–54.9)

90

0

41

0.0 (0.0–0.0)

0.0 (0.0–72.3)

LPV/r + 3TC/ZDV

221

0

95

0.0 (0.0–0.0)

0.0 (0.0–31.5)

70

0

27

0.0 (0.0–0.0)

0.0 (0.0–109.7)

DRV/r + TDF/FTC

224

0

120

0.0 (0.0–0.0)

0.0 (0.0–25.0)

46

1

23

2.3 (0.3–15.4)

43.8 (1.1–244.0)

ATV/r + ABC/3TC

150

0

81

0.0 (0.0–0.0)

0.0 (0.0–37.0)

55

0

26

0.0 (0.0–0.0)

0.0 (0.0–114.4)

RAL + TDF/FTC

174

0

104

0.0 (0.0–0.0)

0.0 (0.0–28.9)

28

0

13

0.0 (0.0–0.0)

0.0 (0.0–222.5)

EFV + TDF/3TC

126

0

70

0.0 (0.0–0.0)

0.0 (0.0–42.7)

30

0

15

0.0 (0.0–0.0)

0.0 (0.0–201.5)

EFV + ABC/3TC

113

0

66

0.0 (0.0–0.0)

0.0 (0.0–45.3)

41

1

19

2.4 (0.3–16.1)

52.2 (1.3–290.8)

7.6 (0.2–42.3) 40.3 (8.3–117.9)

Abbreviations: 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; CI, confidence interval; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; LPV, lopinavir; NRTI, nucleos(t)ide reverse-transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; r, ritonavir; RAL, raltegravir; TDF, tenofovir; ZDV, zidovudine. a

“Other” category includes regimens with 1 antiretroviral class.

DISCUSSION

In this study of HIV-infected patients initiating ART within 2 of the largest integrated healthcare systems in the United States, we found low absolute risks and rates of ALI within the first year of ART. Although liver aminotransferases >200 U/L and grade 3/4 elevations occurred in 2% of the cohort, severe ALI, manifested by coagulopathy and hyperbilirubinemia, developed in 200 U/L compared with initiation of non-NRTI-based ART. The risk was significantly higher for coinfected initiators of darunavir/ritonavir plus tenofovir/emtricitabine, atazanavir/ ritonavir plus tenofovir/emtricitabine, and lopinavir/ritonavir plus zidovudine/lamivudine compared with those initiating efavirenz plus tenofovir/emtricitabine. Among HIV-monoinfected patients, no differences in the risk of this outcome were found among different NRTI combinations; PI, INSTI, or non-NRTI classes; or ART regimens. Taken together, these results highlight

the rarity of antiretroviral-associated ALI and provide evidence for the hepatic safety of these regimens among HIV-infected patients with and without viral hepatitis. As in prior studies of antiretroviral-associated hepatotoxicity in the early ART era [6, 11, 13, 33], viral hepatitis coinfection was associated with higher rates of ALI. Our observation that use of PI-based ART increased the risk of aminotransferase elevations compared with non-NRTI-based ART among viral hepatitis-coinfected patients is consistent with a study of 155 HIV/HCV-coinfected patients from 5 sites across Italy. Protease inhibitor-based ART initiators had a higher incidence of aminotransferase elevations >5 times ULN than non-NRTI-based ART initiators [15]. A  study of 568 HIVinfected patients initiating ART at Johns Hopkins Hospital HIV Clinic found that concurrent PI and non-NRTI use was associated with increased risk of hepatotoxicity among viral hepatitis-coinfected patients [14]. Finally, an analysis of 1982 HIV-infected patients initiating ART at Hospital Carlos III in Spain found that aminotransferase elevations >5 times baseline occurred more commonly in HIV/HCV-coinfected Acute Liver Injury Associated With Antiretrovirals  •  OFID • 7

Table 4.  Risk Factors for Liver Aminotransferases >200 U/L and Severe Acute Liver Injury Among HIV-Infected Individuals Who Were New Initiators of Antiretroviral Therapy Within Kaiser Permanente Northern California (2004–2010) and the Veterans Aging Cohort Study (2004–2012)

Characteristic

Unadjusted HR of Liver Aminotransferases >200 U/L (95% CI)

Adjusted HRa of Liver Aminotransferases >200 U/L (95% CI)

Unadjusted HRb of Severe ALI (95% CI)

Age 18–50 years ≥50 years

Reference

Reference

Reference

1.25 (0.95–1.64)

0.89 (0.66–1.19)

2.66 (1.25–5.69)

Sex Male Female

Reference

Reference

Reference

0.87 (0.45–1.70)

1.11 (0.56–2.21)

2.10 (0.64–6.93)

Race Non-Black Black

Reference

Reference

Reference

1.17 (0.89–1.53)

0.88 (0.66–1.19)

1.44 (0.70–2.96)

Body Mass Index